Roles of Iron-Dependent PHD and JARID in Early-Life Iron Deficiency-Induced Adult Neural Gene Dysregulation

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ABSTRACT Early-life iron deficiency (ID) affects ~20-30% of all pregnant women and their offspring worldwide and causes long-term impairments in cognition and socio-emotional behaviors in adulthood despite iron therapy after the diagnosis of ID in infancy. These persistent abnormalities constitute a significant cost to society in terms of loss of education, job potential, and mental health. The underlying pathobiology for the persistent behavioral abnormalities has been ascribed solely to abnormal neural development and function (e.g., metabolism, dendritogenesis, and synaptogenesis) during critical periods in early life that are carried forward into adulthood (function follows form hypothesis). However, major gaps in knowledge remain, one of which pertains to the iron-dependent cellular mechanisms, by which early-life ID induces the dysregulation of genes critical for neuronal function in adulthood. Such knowledge is critical to advance the field in terms of therapeutic strategies to prevent the long-term negative effects of early-life ID on the developing brain. The present proposal investigates how cellular pathways driven by iron-containing dioxygenases alter long-term neuronal expression of major synaptic differentiation and plasticity genes, including brain-derived neurotrophic factor (BDNF). We leverage the necessity of iron for the catalytic activity of two well-known families of dioxygenases, prolyl hydroxylases (PHDs) and JmjC ARID-domain containing histone demethylases (JARIDs), to analyze the functional effect of early-life ID on these proteins in neural tissues. Our novel conceptualization is that the two pathways are linked through PHD regulation of HIF1α, which in turns targets JARIDs. Based on our recent published findings and new preliminary data, we will show that early-life ID alters the function of both PHD and JARID, leading to stable epigenetic modifications and consequent gene dysregulation in adulthood. We will test this novel hypothesis using our unique chronic iron-deficient primary cultured hippocampal-pyramidal neuron model and our dominant-negative (DN) TfR1 transgenic mouse model that was engineered to induce ID specifically in the developing neurons in a time-dependent manner without systemic anemia or global brain ID. We will further demonstrate the translational value of this concept using the dietary ID anemia rat model that closely resembles the human condition. The proposed work will have a major impact on the field by addressing two important gaps in knowledge: (1) whether PHDs and JARIDs are key iron-containing factors directly responsible for the changes in chromatin structures, resulting in the persistent dysregulation of genes critical for learning and memory; and (2) whether timely iron restoration can attenuate these modifications. Closing these gaps is crucial in designing strategies, including maintenance of iron sufficiency during pregnancy and devising potential therapies that restore the epigenetic landscape (e.g., choline), to lessen the life-long burden of millions of children with early-life ID.